Ketamine transdermal delivery system

ABSTRACT

The present invention is directed to a transdermal delivery device comprising ketamine and formulations thereof. The present invention is also directed to a transdermal delivery device comprising ketamine for the treatment of major depressive disorder (MDD) and/or pain. The present invention is further directed to a transdermal delivery device comprising ketamine and abuse deterrent agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent applicationNo. 62/185,573 filed Jun. 27, 2015.

FIELD OF THE INVENTION

The present invention is directed to transdermal delivery devicescomprising ketamine and formulations thereof. The present invention isalso directed to transdermal delivery devices comprising ketamine forthe treatment of major depressive disorder (MDD) and/or pain. Thepresent invention is further directed to transdermal delivery devicescomprising ketamine and abuse deterrent agents.

BACKGROUND OF INVENTION

Major depressive disorder (MDD) is a disabling psychiatric illness.Lifetime prevalence of MDD is approximately 16%. Kessler et al., JAMA,289(23):3095-105 (2003). There are three primary classes ofantidepressants that are commonly prescribed for NIDD: (I) monoamineoxidase inhibitors (MAOIs), (2) tricyclics, and (3)serotonin-norepinephrine reuptake inhibitors (SNRIs) and selectiveserotonin reuptake inhibitors (SSRIs). There are significant limitationswith the use of current antidepressants, including limited efficacy,delayed onset of action, and adverse side effects. Additionally,antidepressants have been found to be only about 20-30% more effectivethan placebo. The delay of onset varies from weeks to months, which mayresult in adverse events, including hut not limited to increasedvulnerability to suicide, decrease in compliance, and increase in socialand economic burden. Common side effects of these antidepressantsinclude nausea, insomnia, anxiety, weight-loss/gain, drowsiness,headache, loss of sex drive, and/or blurred vision. Penn and Tracey,Ther Adv. Psychopharmacol., 2(5):179-158 (2012).

Pain can present as a disabling physical illness. One type of pain,neuropathic pain, is a complex chronic pain state often accompanied bytissue injury. The occurrence of pain with neuropathic characteristicsis about 6.9-10% of the general population. Hecke et al., Pain,155(4):654-62 (2014). Symptoms of neuropathic pain include spontaneousburning, shooting pain, hyperalgesia, and allodynia. Patients withneuropathic, pain often have conditions that are associated with othersignificant health issues, including depression, sleep problems, andloss of independence. Bouhassira et al., Pain., 136(3):380-7 (2008).Neuropathic pain can be caused by a variety of mechanisms, includinginfection, central or peripheral nerve injury, stroke, multiplesclerosis, diabetes mellitus, sarcoidosis, toxic agents (e.g., alcoholor chemotherapy), inherited or genetic neuropathy, and Complex RegionalPain Syndrome (CRPS). CRPS is an intractable form of pain, oftenresistant to a variety of conventional therapies. Correll et al., PainMed., 5(3):263-75 (2004). Neuropathic pain is difficult to treat, withonly about 40-60% of patients achieving partial relief. Treatment forneuropathic pain includes antidepressants, anticonvulsants, and/ortopical pain management medications. Niesters et al., Expert Opin. DrugMetab. Toxicol., 8(11):1409-17 (2012): Dworkin et al., Pain,132(3):237-51 (2007).

Ketamine is a non-competitive, N-methyl-D-aspartate (NMDA) receptorantagonist, indicated for treatment as an anesthetic, sedative, andanalgesic. Ketamine has been demonstrated to be an effectiveantidepressant, with rapid onset (within about 2 hours ofadministration) and sustained antidepressant effect (from days to insome cases a week or two after administration). Berman et al., Biol.Psychiatry, 47(4):351-54 (2000). The NMDA receptor pathway plays animportant role in pain, including neuropathic pain. Animal studies andhuman clinical studies have shown the efficacy of ketamine in thetreatment of chronic neuropathic pain. Correll et al., Pain Med.5(3):263-75 (2004); Sigtermans et al., Pain, 145(3):304-11 (2009).

Ketamine is a racemic mixture containing R-ketamine and S-ketamine. Itis generally believed that the anesthetic and/or antidepressant effectof ketamine is mainly through the action of S-ketamine because in vitroS-ketamine has about a 4-fold greater affinity than the R-ketamine onNMDA receptor binding. However, animal model studies have suggested thatR-ketamine is more effective as an antidepressant than S-ketamine. inaddition, R-ketamine was shown to be free of psychotomimetic sideeffects and abuse liability. Yang et al., Transl. Psychiatry.,5(e632):1-11 (2015). The present invention is directed towardadministration of the racemic mixture of ketamine; however, embodimentscontaining the R-ketamine or the S-ketamine enantiomers are within thescope of the present invention.

Ketamine is also a known dissociative anesthetic that has gainedpopularity as a drug of abuse, and may be referred to illicitly as “K”or “Special K”. Ketamine is reported to distort perceptions of sight andsound, and make the user feel disconnected. The 2011 “Monitoring theFuture” (MTF) study reports the annual use of ketamine among 8^(th),10^(th) and 12^(th) graders as being 0.8%, 1.2%, and 1.7%, respectively.Johnston, et al., 2012, Monitoring the future national results onadolescent drug use: Overview of key findings, 2011, Ann Arbor:Institute for Social Research, The University of Michigan. Illicitketamine can be distributed as a dried powder or as a liquid, mixed withbeverages, and/or added to smokable materials (such as marijuana ortobacco). As a powder, ketamine can be snorted or pressed into tablets,sometimes in combination with other drugs, including3,4-methylenedioxymethamphetamine (MDMA, referred to illicitly as“ecstasy”), amphetamine, methamphetamine, cocaine, and/or carisoprodol.On Aug. 12, 1999 ketamine became a Schedule III non-narcotic substanceunder the Controlled Substances Act. Consequently, there is a need todevelop abuse deterrent mechanisms to reduce the risk of ketamine abuse.

IV administration of ketamine presents numerous challenges. First, thepatient incurs increased costs to receive IV administration. Second. IVadministration is inconvenient for the patient,and may lead to reducedcompliance. Third, the rapid initial rise in ketamine plasmaconcentrations following IV administration to the maximum plasmaconcentration (C_(max)) can cause adverse side effects, including drugtoxicity, psychotomimetic problems, and increased potential foraddiction. Moreover, because ketamine has a short half-life (about 2hours), this immediate release delivery of ketamine by IV administrationmay result in little to no ketamine remaining in plasma after about 4-8hours, necessitating frequent and repeated dosing to maintaintherapeutic plasma levels. Fourth, without additional safeguards, IVadministration of ketamine may be susceptible to abuse.

An intranasal formulation of the S-enantiomer of ketamine, esketamine,is under development and in clinical study by Janssen. US 2011/0236573A1, Singh et at., Esketamine For The Treatment of Treatment-RefractoryOr Treatment-Resistant Depression. However, intranasal delivery ofketamine presents numerous challenges. It suffers from many of the sameimmediate release issues faced by IV administration of ketamine, namely,rapid onset of maximum concentration (T_(max)), high C_(max), increasedrisk of side effects like drug toxicity, and the need for frequent andmultiple dosing to maintain therapeutic plasma concentrations, Frequentadministration of intranasal ketamine may increase the risk ofirritating and damaging the nasal epithelium, which in turn may reducepatient compliance, Also, intranasal administration is associated withhigh variability in absorption among subjects. Kublik et al., Adv. DrugDeliv. Rev. 29:157-77 (1998). Further, the rapid rise in ketamine plasmaconcentration following intranasal administration may cause adverse sideeffects, such as drug toxicity. Moreover, intranasal delivery ofketamine, without additional safeguards, is highly susceptible to abuse.Other routes of administration of ketamine, including parenteraladministration of ketamine (e.g., subcutaneous, intramuscular, etc.)suffer from many of these same challenges.

While oral administration (i.e., tablet or capsule) is typicallyconvenient for the patient, the metabolic arid pharmacokineticproperties of ketamine make oral administration less suitable. Ketaminehas a high systemic (primarily hepatic) clearance of about 19 ml/min·kg,a rate which approaches liver plasma flow. Thus, ketamine is subject tosubstantial pre-systemic metabolism, or first-pass effect, in the liverand gut wall by metabolic enzymes, such as cytochrome P450 enzymes(CYP450). Consequently, the absolute oral bioavailability of ketamine inhumans is only about 10-20%. Due to this first-pass effect, there is anincreased risk for drug-drug interactions (DDI) with drugs that caninhibit or induce CYP450s. Clements et al., J Pharm Sci, 71(5):539-42(1981); Fanta, et al., Eur. Clin, Pharmacol., 71:441-47 (2015);Peltoniemi et al., Basic & Clinical Pharmacology & Toxicology,111:325-332 (2012). Moreover, ketamine tablets or capsules are easilyabused.

SUMMARY OF THE INVENTION

The present invention is directed to transdermal delivery devicescomprising ketamine and formulations thereof. The present invention isalso directed to transdermal delivery devices comprising ketamine forthe treatment of major depressive disorder (MDD) and/or pain. There arelong-felt and unmet medical needs for the treatment of MDD and for thetreatment of pain, which are fulfilled by the present invention. Thecontrolled, prolonged, and steady ketamine exposure to humans from thetransdermal delivery device of the present invention can reduce adverseside effects compared with other routes of ketamine delivery, includingbut not limited to intravenous (IV) administration and intranasal spray.Because ketamine has high abuse potential, the present invention isfurther directed to transdermal delivery devices comprising ketamine andabuse deterrent agents.

The present invention has numerous advantages. Formulations of thetransdermal delivery device provide excellent ketamine permeability andstability. The inventors discovered, through in vitro experiments, thatketamine has excellent transdermal permeability properties, which arevery important for efficacious clinical use. Additional in vitroexperiments demonstrated that adding, for example, crystallizationinhibitors to formulations of the present invention resulted in verystable transdermal delivery devices, which is important when making apharmaceutical product.

Additionally, the present invention provides improved drug metabolismand pharmacokinetic properties compared with other methods ofadministering ketamine, such as IV and intranasal administration. First,transdermal delivery avoids the aforementioned first-pass effect.Second, it reduces the aforementioned DDI risk. Third, it delivers asustained in vitro release profile, and therefore, a steadier in vivoplasma concentration versus time profile over a longer period of time.In other words, there is no need for frequent, multiple dosing for daysor weeks to maintain therapeutic plasma concentrations of ketamine, asmay be the case with, for example, IV infusion. Correll et al., PainMed. 5(3):263-75 (September 2004). Instead, the present invention canmeet the desired prolonged drug absorption profile. For example,administration of a single transdermal delivery device of the presentinvention can deliver a relatively constant ketamine plasmaconcentration for up to about 7 days. Fourth, the present inventiondelivers lower C_(max) values for ketamine in the plasma, as well asminimal fluctuation between C_(max) and C_(min), thereby reducingadverse side effects, including but not limited to toxicity,psychotropic effects, increased potential for addiction, and lack oftherapeutic effect.

The transdermal delivery device of the present invention providesflexibility in dose, dosage release rate, patch size, and duration ofapplication to allow for optimization. Transdermal delivery devicesaccording to the present invention include, but are not limited to,transdermals and dermal patches, topical skin applications such asspray, creams, gels, lotions, dressings and liquid solutions, and othertransdermal delivery systems and dosage forms known to persons skilledin the art. For example, these flexible parameters can be adjusted bythe formulator and/or the clinician to provide the optimal ketamineplasma concentration-time profile for the individual patient thatmaximizes efficacy and minimizes adverse side effects. Therefore, theketamine transdermal delivery device of the present invention isparticularly effective for the treatment of MDD and pain.

Moreover, the present invention improves convenience and compliancecompared with other forms of administering ketamine. For example,administration of the transdermal delivery device once or twice a weekis more convenient than, for example, multiple daily doses of immediaterelease forms of ketamine. Immediate release ketamine or immediaterelease ketamine formulation means administration of ketamine that isnot extended, controlled, delayed or prolonged. Dose equivalent withmeans that the total dosage of drug administered between the compareditems is the same. Also, the present invention is less invasive and lesscostly than IV administration. The present invention causes lessirritation and is less invasive than intranasal administration. Further,the present invention is less likely to cause drug toxicity thanimmediate release forms of drug delivery.

The present invention also has advantages with respect to abusedeterrence. The transdermal delivery device itself may serve as an abusedeterrent because it is more difficult to abuse directly, such as bybiting or swallowing the device. Specifically, the ketamine isincorporated into a polymeric matrix together with other excipients,including, but not limited to skin permeation enhancers, humectants,plasticizers, buffers, antioxidants, and combinations thereof, each ofwhich may inhibit ketamine extraction for abuse. Nevertheless, specific,additional abuse deterrent agents can be added to formulations of thepresent invention to further deter abuse.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a ketamine transdermal delivery device without abuse deterrentproperties.

FIG. 2 is a transdermal delivery device comprising ketamine with abusedeterrent properties.

FIG. 3 is an alternate embodiment of a transdermal delivery devicecomprising ketamine and abuse deterrent agents.

FIG. 4 is an alternate embodiment of a transdermal delivery devicecomprising ketamine and abuse deterrent agents.

FIGS. 5-7 are ketamine plasma concentration versus time profiles inhumans for Example 2 of the present invention using different sizes ofthe transdermal delivery device. These pharmacokinetic profiles arepredicted by known convolution methodology using in vitro transdermalpermeation data and in vivo intravenous plasma concentration data.

FIG. 8 is a graph of the in vitro skin permeation of ketamine in a FranzDiffusion Cell model for the transdermal delivery device according toExample 2.

FIG. 9 is a 6-month stability graph of the present invention prepared inaccordance with Example 5.

FIGS. 10-13 are ketamine plasma concentration versus time profiles inhumans corresponding to the transdermal delivery devices of Table 2.These transdermal delivery devices are for the treatment of MDD. Thesepharmacokinetic profiles are predicted by known convolution methodologyusing in vitro transdermal permeation data and in vivo intravenousplasma concentration data.

FIGS. 14-17 are graphs of the pharmacokinetic plasma concentrationsversus time profiles, corresponding to the transdermal delivery devicesof Table 3, These transdermal delivery devices are for the treatment ofpain. These pharmacokinetic profiles are predicted by known convolutionmethodology using in vitro transdermal permeation data and in vivointravenous plasma concentration data.

DETAILED DESCRIPTION OF THE INVENTION

The active ingredient in the transdermal delivery device of the presentinvention is preferably employed at about 1-35% by weight of the finalformulation (also referred to as 1-35 weight percent) and mostpreferably 10-25% by weight of the final formulation. The most preferredactive ingredient is ketamine. Additional active ingredients that can beemployed in the present invention can be chosen from drugs thatcounteract the potential adverse effects of ketamine, reduce ketamineaddiction potential, and/or enhance ketamine's antidepressant effectand/or pain management effects. All weight percentages provided in thepresent disclosure are based on the weight of the final formulation,which includes the adhesive-drug layer (or adhesive-drug matrix) and theabuse deterrent layer (or abuse deterrent matrix, which is optional),but not the release liner or the backing film.

The transdermal permeation rate (mg/day) combined with the size of thetransdermal delivery device and the duration of application of thetransdermal delivery device determines the plasma concentration of thedrug. The transdermal permeation rate of the ketamine transdermaldelivery device of the present invention will preferably be about 0.1-30mg/day/cm² of the transdermal delivery device, and most preferably about0.5-5 mg/day/cm². The size of transdermal delivery device willpreferably be about 5 -300 cm². The duration of application of thetransdermal devices will preferably be about 8-168 hours. Combinationsof these preferred ranges provide prolonged plasma concentrations ofketamine ranging from about 0.4-3850 ng/ml. The plasma concentrations ofketamine will reach near steady-state at about 8 hours afteradministration and will be sustained for the duration of theapplication.

Preferred transdermal permeation transdermal delivery device sizes, anddurations of applications for the transdermal delivery devices of thepresent invention are set forth in Table 1.

TABLE 1 Transdermal delivery Application Dosage Plasma concentrationsPermeation rates device size Duration strength after about 8 hours(ng/day/cm²) (cm²) (days) (mg) (ng/ml) 0.1-30 10 1/3 0.33-100  0.43-128 0.1-30 300 1/3  110-3000  13-3850 0.1-30 10 1  1-300 0.43-128  0.1-30300 1  30-9000  13-3850 0.1-30 10 7   7-2100 0.43-128  0.1-30 300 7 210-63000  13-3850

The plasma concentrations of ketamine versus time are calculated basedon the reported pharmacokinetic parameters of ketamine in humans.Ketamine follows a three-compartment model with the parameters for a70-kg human as follows: clearance=79.8 (liter/hour); V1=133 liter; andmicro constants k₁₂=0.174 hour⁻¹, k₁₃=1.18 hour⁻¹, k₂₁=0.124 hour⁻¹,k₃₁=1.59 hour⁻¹. Fanta, et al., Eur. J. Clin. Pharmacol., 71:441-447(2015). There is variability among human populations and individuals,such that the pharmacokinetics of each human are not the same, and forcertain populations and for some individuals, the pharmacokinetics candeviate significantly. Plasma concentrations provided by any givendosage strength for the transdermal delivery device of the presentinvention can vary from individual to individual.

For antidepressant effect (i.e., the treatment of MDD) with minimizedadverse side effects, the preferred plasma concentration range ofketamine is from about 10-200 ng/ml, and the most preferred plasmaconcentration range is from about 10-100 ng/ml.

Table 2 provides ranges for the most preferred transdermal permeationrates, transdermal delivery device sizes, and duration of application ofthe transdermal delivery devices for antidepressant effect (i.e., thetreatment of MDD) with minimized adverse side effects. These ranges arechosen to provide prolonged plasma concentrations of ketamine rangingfrom about 10 -200 ng/ml for about 8-168 hours, and the most preferredplasma concentrations are from about 10-100 ng/ml. Variations on thetransdermal delivery devices comprising ketamine designed for thetreatment of MDD will contain from about 8.3-200 mg and be applied forabout 8 hours, from about 25-600 mg and be applied for about 24 hours,from about 87.5-2100 mg and be applied for about 84 hours, and fromabout 175-4200 mg and be applied for about 168 hours.

Transdermal delivery devices for the treatment of MDD are prepared withdosage strengths from about 8.3-200 mg, and are designed to be appliedfor about 8 hours, which will provide a plasma concentration of ketaminefrom about 11-257 ng/ml. An alternate embodiment of the presentinvention for the treatment of MDD is designed to provide reducedadverse side effects. The reduced adverse side effects are provided by atransdermal delivery device according to the present invention preparedwith dosage strengths of ketamine from about 8.3-100 mg of ketamine,designed to be applied for 8 hours, and to provide a plasmaconcentration of ketamine from about 11-128 ng/ml.

Transdermal delivery devices for the treatment of MDD according to thepresent invention are prepared with dosage strengths from about 25-600mg and are designed to be applied for about 24 hours, which will providea plasma concentration of ketamine from about 11-257 ng/ml. An alternateembodiment of the present invention for the treatment of MDD is designedto provide reduced adverse side effects. The reduced adverse sideeffects are provided by a transdermal delivery device according to thepresent invention prepared with dosage strengths of ketamine from about25-300 mg of ketamine, designed to be applied for 24 hours, and toprovide a plasma concentration of ketamine from about 11-128 ng/ml.

Transdermal delivery devices for the treatment of MDD according to thepresent invention are prepared with dosage strengths from about87.5-2100 mg, and are designed to be applied for about 84 hours, whichwill provide a plasma concentration of ketamine from about 11-257 ng/ml.An alternate embodiment of the present invention for the treatment ofMDD is designed to provide reduced adverse side effects, The reducedadverse side effects are provided by a transdermal delivery deviceaccording to the present invention prepared with dosage strengths ofketamine from about 87.5-1050 mg, designed to be applied for about 84hours, and to provide a plasma concentration of ketamine from about11-128 ng/ml.

Transdermal delivery devices for the treatment of MDD according to thepresent invention are prepared with dosage strengths from about 175-4200mg, and are designed to be applied for about 168 hours, which willprovide a plasma concentration of ketamine from about 11-257 ng/ml. Analternate embodiment of the present invention for the treatment of MDDis designed to provide reduced adverse side effects. The reduced adverseside effects are provided by a transdermal delivery device according tothe present invention prepared with dosage strengths of ketamine fromabout 175-2100 mg, designed to be applied for about 168 hours, and toprovide a plasma concentration of ketamine from about 11-128 ng/ml.

TABLE 2 Transdermal delivery Application Dosage Plasma concentrationsPermeation rates device size Duration strength after about 8 hours(mg/day/cm²) (cm²) (days) (mg) (ng/ml) 1  25-300 1/3  8.3-100   11-128 5 5-60 1/3  8.3-100   11-128 5   5-120 1/3  8.3-200   11-257 1  25-300 1 25-300  11-128 5  5-60 1  25-300  11-128 5   5-120 1  25-600  11-257 1 25-300 3.5  87.5-1050  11-128 5  5-60 3.5  87.5-1050  11-128 5   5-1203.5  87.5-2100  11-257 1  25-300 7  175-2100  11-128 5  5-60 7  175-2100 11-128 5   5-120 7  175-4200  11-257

For pain management, with minimized adverse events, the preferred plasmaconcentrations ranges of ketamine are from about 50-1000 ng/ml, and themost preferred plasma concentration is about 500 ng/ml.

Table 3 provides ranges for transdermal permeation rates, transdermaldelivery device sizes, and duration of application of the transdermaldelivery devices for pain management. These ranges are chosen to provideurged plasma concentrations of ketamine ranging from about 50-1000ng/ml, and for about 8-168 hour, and the most preferred plasmaconcentration is about 500 ng/ml. Transdermal delivery devicescomprising ketamine designed for pain management will contain about40-500 mg and be applied for about 8 hours, from about 120-1500 mg andbe applied for about 24 hours, from about 420-5250 mg and be applied forabout 84 hours, and from about 840-10500 mg and be applied for about 168hours.

Transdermal delivery devices for the treatment of pain according to thepresent invention are prepared with dosage strengths from about 40-500mg, are designed to be applied for about 8 hours, and will provide aplasma concentration of ketamine from about 51-642 ng/ml.

Transdermal delivery devices for the treatment of pain according to thepresent invention are prepared with dosage strengths from about 120-1500mg, are designed to be applied for about 24 hours, and will provide aplasma concentration of ketamine from about 51-642 ng/ml.

Transdermal delivery devices for the treatment of pain according to thepresent invention are prepared with dosage strengths from about 420-5250mg, are designed to be applied for about 84 hours, and will provide aplasma concentration of ketamine from about 51-642 ng/ml.

Transdermal delivery devices for the treatment of pain according to thepresent invention are prepared with dosage strengths from about840-10,500 mg, are designed to be applied for about 168 hours, and willprovide a plasma concentration of ketamine from about 51-642 ng/ml.

TABLE 3 Transdermal delivery Application Plasma concentrationsPermeation rates device Size Duration Dosage after about 8 hours(mg/day/cm²) (cm²) (day) strength (ng/ml) 1 120-300 1/1  40-100 51-128 5 24-300 1/3  40-500 51-642 1 120-300 1 120-300 51-128 5  24-300 1 120-1500 51-642 1 120-300 3.5  420-1050 51-128 5  24-300 3.5  420-525051-642 1 120-300 7  840-2100 51-128 5  24-300 7   840-10500 51-642

Preferably, the transdermal delivery device of the present inventionwill be administered once a day, twice a week, or once a week. Thedosing regimen of the present invention is not limited to the examplesprovided in Tables 2 and 3 for antidepressant effect and painmanagement. In accordance with the need of the patient and as determinedby the physician, the dose frequencies, device size, and/or dosagestrength can be adjusted. For example, the application of thetransdermal delivery device can be for a duration shorter than 8 hours,such as 4 hours. The ketamine plasma concentrations at about 4 hoursafter administration will be about 80% of the plasma concentration atabout 8 hours, which can provide effective anti-depressant and/or painmanagement, depending on the need of the patient.

The plasma drug concentrations profiles in Table 4 and illustrated inFIGS. 6-7, are exemplary of the plasma profiles of the presentinvention. The plasma drug concentration profiles in Tables 2 and 3 andillustrated at least in 10-17, are further exemplary of the plasmaprofiles of the present invention. These plasma profiles rise slowly andare maintained at a relatively constant level for a prolonged period oftime. On the contrary, IV and intranasal ketamine will generally providea C_(max) approximately 3 to 10 times higher than the C_(max) providedby a transdermal delivery device of the present invention (at equivalentdoses), while the area under the curve (AUC) is constant (e.g., FIG. 5).Additionally, the prolonged and steady administration of ketamineprovided by the transdermal delivery device of the present inventionexhibits minimal fluctuations in plasma concentration relative tomultiple doses of IV or intranasal administration of ketamine. Thisreduction or minimization of plasma fluctuations in turn reduces theoccurrence of adverse side effects resulting from under and overmedication. Consequently, the plasma profile provided by the presentinvention is improved and may result in better therapeutic outcomes andgreater patient compliance.

The structure and packaging of the transdermal delivery device of thepresent invention are prepared in accordance with methods and techniquesknown to persons skilled in the art. The primary components are thebacking layer, the adhesive-drug layer (or adhesive-drug matrix), theabuse deterrent layer (or abuse deterrent matrix) (optional), and therelease liner.

The backing layer may be comprised of polymeric films such as polyester(PET) or polyethylene (PE) films that support the adhesive drug matrixand protect the transdermal delivery device from the environment. Thepreferred thickness range for the backing film is from about 2-5 mils (1mil equals 1/1000 of an inch), and the most preferred thickness range ofthe backing layer is from about 3-4 mils thick.

The adhesive in the adhesive-drug layer may be a pressure sensitiveadhesive (PSA). Tan et al., Pharm Sci. & Tech Today, 2:60-69 (1999).Useful PSAs in transdermal delivery systems include, but are not limitedto, polyisobutylenes (PIB), silicone polymers, and acrylate copolymers,such as acrylic pressure sensitive adhesives, including Duro-Tak87-2516, 87-2852 and 87-2194, manufactured by Henkel Adhesives. PIBs areelastomeric polymers that are commonly used in PSAs, both asprimary-base polymers and as tackifiers. PIBs are homopolymers ofisobutylene and feature a regular structure of a carbon hydrogenbackbone with only terminal unsaturation. PIBs are marketed under thetrade name Oppanol by BASF. The silicone polymers are a high molecularweight polydimethylsiloxane that contains residual silanol functionality(SiOH) on the ends of the polymer chains. Silicone PSAs for use inpharmaceutical applications are available from Dow Corning Corporation,for example wider the trade name of BIO-PSA. The PSA is preferablyemployed at about 30-90% by weight of the final formulation, and mostpreferably about 40-60% by weight of the final formulation.

The release liner can be manufactured in the desired size for thepresent invention. The release liner may be comprised of silicone orfluoro-polymer coated polyester film. The release liner protects thetransdermal delivery device during storage and is removed before itsuse. Silicone-coated release liners are manufactured by MylanCorporation, Loparex Corporation, and 3M's Drug Delivery Systems. Thefluoro-polymer coated release liners are manufactured and supplied by3M's Drug Delivery Systems and Loparex. The preferred thickness of therelease liner is about 2-10 mils, and most preferably about 3-5 mils.

Additional drugs can be incorporated in the transdermal delivery deviceto counteract adverse effects, and/or to enhance the antidepressant orpain management effect of ketamine. Examples for enhancingantidepressant effect include, but are not limited to, antagonists ofgroup II metabotropic glutamate receptors, such as LY341495, Podkowa etal., Psychopharmacology (Berl) (Jun. 11, 2016). Examples for reducingside effects with ketamine, especially psychotomimetic andsympathomimetic, include, but not limited to, co-administration ofalpha-2 agonists such as clonidine, Lenze, World J Biol Psychiatry,17(3):230-8 (2016). If an additional drug is employed in the presentinvention, it is preferably employed at about 0.1-20% by weight of thefinal formulation, and most preferably about 1-5% by weight of the finalformulation.

Additional components can be added to the transdermal delivery device ofthe present invention to optimize it. Skin permeation enhancers areemployed to enhance the skin permeability of the drug through the skin.Skin permeation enhancers that may be employed in the present inventioninclude, but are not limited to, sulphoxides (e.g. dimethylsulphoxide,DMSO), Azones (e.g. laurocapram), pyrrolidones (e.g. 2-pyrrolidone, 2P),alcohols and alkanols (ethanol, or decanol), glycols (e.g, propyleneglycol (PG)), surfactants and terpenes, Williams et al., Adv Drug DelivRev. 27; 56(5):603-18 (2004). The skin permeation enhancers arepreferably employed at about 1-20% by weight of the final formulation,and most preferably about 4-10% by weight of the final formulation.

Humectants are employed to keep the transdermal delivery device hydratedand/or to reduce the loss of moisture. The humectants that may beemployed in the present invention include, but are not limited to,propylene glycol, glycerol, urea, polyvinylpyrrolidone (PVP),vinylpyrrolidone-vinyl acetate copolymers, and copolymers of PVP (e.g.,BASF's Kollidon K30, K12, Kollidon VA 64, or Kollidon CL-M, magnesiumsilicate, and silica. The humectants are preferably employed at about2-20% by weight of the final formulation and most preferably about 5-10%by weight of the final formulation.

Plasticizers are employed in transdermal drug delivery systems to obtaindesirable mechanical properties, such as to improve the film formingproperties and the appearance of the film, to decrease the glasstransition temperature of the polymer, to prevent film cracking, and toincrease film flexibility. The plasticizers that may be employed in thepresent invention include, but are not limited to, phthalate esters,phosphate esters, fatty acid esters, and glycol derivatives. Theplasticizers are preferably employed at about 2-20% by weight of thefinal formulation and most preferably about 5-10% by weight of the finalformulation. Designing and Characterization of Drug Free Transdermaldelivery devices for Transdermal Application, International Journal ofPharmaceutical Sciences and Drug Research, Vol. 2, No. 1, pp. 35-39Bharkatiya, M.; Nema, R. K. & Bhatnagar, M. (2010) Wypch, G. (2004) andHandbook of Plasticizers, Chem Tec, 437-440, ISBN 1-895198-29-1,Ontario, Canada.

Antioxidants are employed to prevent drug degradation by oxidationAntioxidants that may be employed in the present invention include, butare not limited to, butylated hydroxyanisole (BHA), butylhydroxy toluene(BHT), tert-Butylhydroquinone, ascorbic acid, and tocopherols. Theantioxidants are preferably employed at about 0.01-5% by weight of thefinal formulation and most preferably about 0.1-1.0% by weight of thefinal formulation.

Anti-irritants are employed to provide alleviation or prevention of skinirritation, and to assist in the release of the active ingredients.Anti-irritants that may be employed in the present invention include,but are not limited to, aloe, arnica, chamomile, cucumber, menthol,mugwort, oat, zinc oxide, drug release modifiers such as chitosan,cellulose-based polymers, silicon dioxides, and polymethacrylates.

Other suitable excipients useful in the preparation of transdermaldelivery devices are within the knowledge of those skilled in the art,and can be found in the Handbook of Pharmaceutical Excipients, (7^(th)ed. 2012), the entire content of which is hereby incorporated byreference.

FIG. 1 is an embodiment of the transdermal delivery device in which thebacking film (1) is affixed atop the adhesive drug matrix (2), which issupported by a release liner (3). The adhesive drug matrix contains thedrug and adhesive, as well as enhancers, humectants, plasticizers,antioxidants, pH modifiers, crystallization inhibitors, and otheringredients that aid in drug release and permeation through skin, and inmaintaining drug stability.

FIG. 2 is an example of a transdermal delivery device that contains anabuse deterrent agent (4) that is not skin permeable, drug (5) dissolvedin the adhesive-drug matrix (2), a transdermal delivery device backingfilm (1), and a release liner (3).

FIG. 3 is a transdermal delivery device that contains a hacking film(1), an abuse detenent layer (6), an adhesive-drug matrix (2), and arelease liner (3). The abuse deterrent layer is capable of releasing an.abuse deterrent agent upon tampering with the transdermal deliverydevice. In an embodiment in which the abuse deterrent layer comprises agel forming agent, the gel forming agent can form a gel solution uponextraction.

FIG. 4 is an embodiment of a prolonged use, e.g., 7-day transdermaldelivery device, with abuse deterrent agents in a segregated, abusedeterrent layer. FIG. 4 shows the hacking film (1), and overlay adhesivelayer (7), an abuse deterrent layer (6), the adhesive-drug layer (2),and a release liner (3). The overlay adhesive layer extends over theouter edges of the drug-adhesive layer (2) and the abuse deterrent layer(6) to provide added adhesion to the skin for prolonged use. Embodimentsof the present invention can be prepared with an overlay adhesive layer(7) with or without an intervening abuse deterrent layer (6).

Table 4 provides estimated plasma concentrations for transdermaldelivery devices prepared according to the present invention. The plasmaconcentration are exemplified in FIGS. 5, 6 and 7, which are describedbelow in detail.

TABLE 4 FIG. 5 IV after 24-hr FIG. 6 FIG. 7 (ng/ml) 24-hr Device 8-hrDevice Time IV 9.4-cm², 24-hr (ng/ml) (ng/ml) (hr) (0.5 mg/kg) (0.5mg/kg) 10-cm² 100-cm² 300-cm² 10-cm² 100-cm² 300-cm² 0 0 0 0 0 0 0 0 0 1110 5.8 6.2 62 186 6.2 62 186 2 62 8.7 9.2 92 276 9.2 92 276 3 43 11 11113 338 11 113 338 4 31 12 13 127 382 13 127 382 5 23 13 14 138 414 14138 414 6 17 14 15 146 439 15 146 439 7 14 14 15 153 458 15 153 458 8 1115 16 158 473 16 158 473 9 8.9 15 16 162 485 10 102 305 10 7.4 16 17 165495 7.5 75 223 11 6.4 16 17 168 504 5.7 57 169 12 5.5 16 17 170 511 4.444 132 13 4.9 16 17 173 518 3.5 35 106 14 4.3 16 17 175 524 2.9 29 87 153.9 17 18 176 529 2.4 24 73 16 3.5 17 18 178 534 2.1 21 63 17 3.2 17 18179 538 1.8 18 54 18 2.9 17 18 181 542 1.6 16 48 19 2.6 17 18 182 5461.4 14 43 20 2.4 17 18 183 549 1.3 13 38 21 2.2 17 18 184 552 1.2 12 3522 2.0 17 18 185 554 1.0 10 31 23 1.8 17 19 186 557 0.95 9.5 28 24 1.718 19 186 559 0.86 8.6 26 25 1.5 12 13 125 375 0.79 7.9 24 26 1.4 9.09.6 96 287 0.72 7.2 21 27 1.3 7.1 7.6 76 227 0.65 6.5 20 28 1.2 5.8 6.161 184 0.60 6.0 18 29 1.1 4.8 5.1 51 154 0.55 5.5 16 30 0.97 4.1 4.3 43130 0.50 5.0 15 31 0.88 3.5 3.8 38 113 0.46 4.6 14 32 0.81 3.1 3.3 33 990.42 4.2 13 33 0.74 2.7 2.9 29 88 0.38 3.8 11 34 0.68 2.5 2.6 26 78 0.353.5 10 35 0.62 2.2 2.3 23 70 0.32 3.2 9.6 36 0.57 2.0 2.1 21 64 0.29 2.98.8 37 0.52 1.8 1.9 19 58 0.27 2.7 8.0 38 0.47 1.6 1.7 17 52 0.24 2.47.3 39 0.43 1.5 1.6 16 48 0.22 2.2 6.7 40 0.40 1.4 1.5 15 44 0.21 2.16.1 41 0.36 1.2 1.3 13 40 0.19 1.9 5.6 42 0.33 1.1 1.2 12 36 0.17 1.75.1 43 0.30 1.0 1.1 11 33 0.16 1.6 4.7 44 0.28 0.95 1.0 10 30 0.14 1.44.3 45 0.25 0.87 0.92 9.2 28 0.13 1.3 3.9 46 0.23 0.79 0.85 8.5 25 0.121.2 3.6 47 0.21 0.73 0.77 7.7 23 0.11 1.1 3.3 48 0.19 0.66 0.71 7.1 210.10 1.0 3.0

Table 5 provides the cumulative amount of ketamine that permeates humanskin in the Franz Diffusion Cell model disclosed in FIG. 8, as providedby a transdermal delivery device according to Example 2 of the presentinvention. The total amount of drug in the transdermal delivery deviceof Example 2 is 4.75 mg. Therefore, the transdermal bioavailability ofExample 2 within 24 hours is about 78%.

TABLE 5 Cumulative ketamine Time permeated (hr) (mg/cm²) 2 0.0976 40.307 8 1.13 12 1.98 24 3.72

Transdermal delivery devices can be abused. One method of abuse is toplace the device in a solvent to separate the drug from the polymericmatrix, followed by separating the drug from any additional components.In order to deter abuse, the present invention is further directedtowards a novel transdermal delivery device comprising ketamine andabuse deterrent agents.

Abuse deterrent agents are employed because they have one or more of thefollowing properties: (1) unpalatable bitterness or other repulsivetastes in the mouth (i.e., bittering agents); (2) formation of gel uponmixing with the extraction solvents (i.e., gel forming agents); (3)severe irritation when injected (i.e., irritants); (4) mood depression(e.g., droperidol) or other pronounced central nervous system (CNS)effects; (5) acute gastrointestinal, cardiac or respiratory effects; (6)violent nausea or vomiting; (7) repugnant smells if not used asinstructed; (8) sleep inducing, thereby causing the abuser to miss or bemade unaware of the euphoria; and/or (9) deactivation or degradation ofthe active ingredient (i.e., strong oxidation agents (such as hydrogenperoxide), strong acid, or strong base, and/or antagonists) uponattempted extraction. The abuse deterrent agent is employed at about0.01-10% by weight of the final formulation, preferably about 0.1-4% byweight, and most preferably about 0.1-0.5% by weight.

The abuse deterrent agents can be included in the adhesive drug matrixor in a separate abuse deterrent layer (also referred to as the abusedeterrent matrix). The abuse deterrent layer may be comprised of acombination of polymer and the abuse deterrent agent. Additionally, theabuse deterrent layer can be the abuse deterrent agent itself becausemany of the recited polymers also act as gel forming agents. Suitablepolymers include, but are not limited to, one or more pharmaceuticallyacceptable polymers that will undergo art increase in viscosity uponcontact with a solvent. Preferred polymers include polyethylene oxide,polyvinyl alcohol, hydroxypropyl methylcellulose, carbomers (carbopol),polyvinylpyrrolidone (PVP), and/or other cellulose polymers. In oneembodiment of the present invention the polymer includes polyethyleneoxide. The polyethylene oxide can have an average molecular weightranging from about 300,000-5,000,000, and more preferably from about600,000-5,000,000, and most preferably at least about 5,000,000. In oneembodiment, the polyethylene oxide is a high molecular weightpolyethylene oxide. Examples of suitable, commercially availablepolyethylene oxide polymers include Polyox®, WSRN-1105 and/or WSRcoagulant, available from Dow Chemical. The preferred weight range ofthe polymer is from about 1-40% by weight of the final formulation, andthe most preferred range of the polymer is from about 2-10% by weight ofthe final formulation.

Bittering agents are pharmaceutically acceptable hitter substances thatcreate a hitter taste or effect when administered nasally (snorted),orally, buccally or sublingually, making consumption difficult. Thebittering agents that may be employed in the present invention include,but are not limited to, sucrose octaacetate (used as a denaturant foralcohol) (e.g., SD-40), den atonium saccharide, denatonium benzoate,caffeine, quinine (or a quinine salt such as quinine sulfate), bitterorange peel oil, and other botanical extract ingredients, such as pepperextract (cubeb), capsicum, and the like. Preferred bittering agents aresucrose octaacetate, denatonium benzoate (Bitrex), and denatoniumsaccharide (four times more bitter than denatonium benzoate) becausethey are extremely bitter even at low concentrations and are essentiallynon-toxic. The bittering agent is employed at about 0.01-10% by weightof the final formulation, preferably about 0.1-4% by weight, and mostpreferably about 0.1-0.5% by weight.

Gel forming agents are employed to form a gel structure upon mixing withthe extraction solvents and, thus, provide abuse deterrent properties.Specifically, gel forming agents are compounds that upon contact with asolvent (e.g., water or alcohol), absorb the solvent and swell, therebyforming a viscous or semi-viscous substance that significantly reducesand/or minimizes the amount of free solvent which can contain an amountof solubilized drug, and which minimizes what can be drawn into asyringe for injection (i.e., IV or intramuscular). The gel can alsoreduce the overall amount of drug extractable with the solvent byentrapping the drug in a gel matrix. In certain embodiments the gelforming agent can be in a segregated abuse deterrent layer laminated tothe adhesive drug matrix.

The gel forming agents that may be employed include, but are not limitedto, ethyl cellulose, cellulose acetate, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate, cellulosetriacetate, cellulose ether, cellulose ester, cellulose ester ether,acrylic resins comprising copolymers synthesized from acrylic andmethacrylic acid esters, the acrylic polymer may be selected from thegroup consisting of acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethylmethacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), poly methacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), glycidylmethacrylate copolymers, and mixtures thereof. The gel forming agent ispreferably employed at about 3-40% by weight of the final formulation,and the most preferably about 5-20% by weight of the final formulation.

In embodiments of the present invention the gel forming agent includespolyvinyl alcohol with a molecular weight ranging from about20,000-200,000, specific gravity ranging from about 1.19-1.31, andviscosity ranging from about 4-65 cps. The polyvinyl alcohol used in theformulation is preferably a water-soluble synthetic polymer representedby —(—C₂H₄O—)_(n)—, where n can range from about 500-5,000. Examples ofsuitable, commercially available polyvinyl alcohol polymers include PVA,USP, available from Spectrum Chemical Manufacturing Corporation, NewBrunswick, N.J. 08901.

In embodiments of the present invention, the gel forming agent includeshydroxypropyl methyl cellulose (Hypromellose) with a molecular weightranging from about 10,000-1,500,000, typically from about 5000-10,000(i.e., low molecular). The specific gravity of the hydroxypropyl methylcellulose ranges from about 1.19-1.31, with an average specific gravityof about 1.26. Viscosity of the hydroxypropyl methyl cellulose is about3600-5600 cPs. The hydroxypropyl methylcellulose used in the formulationcan be a water-soluble synthetic polymer. Examples of suitable,commercially available hydroxypropyl methylcellulose polymers includeMethocel K100 LV and Methocel K4M, available from Dow chemicals.

In other embodiments of the present invention the gel forming agentincludes hydrophilic polymers, such as hydrogels, which providesviscosity to the dosage form upon tampering. In such embodiments, whenan abuser crushes and dissolves the dosage form in a solvent (e.g.,water or saline), a viscous or semi-viscous gel is formed.

In certain embodiments of the present invention, the gel forming agentcan include carbomers, having a molecular weight ranging from700,000-4,000,000 and viscosity ranging from about 4000-39,400 cPs.Carbomer is preferably employed in the present invention from about1-40% by weight of the final formulation, and most preferably from about2-10% by weight. Examples of suitable, commercially available carbomersinclude carbopol 934P NF, carbopol 974P NF, and carbopol 971P NF,available from Lubrizol.

Irritants are pharmaceutically inert compounds that induce irritation tothe mucous membranes of the body (s.e., nasal, mouth, eye, intestine,urinary tract). The irritants that may be employed in the presentinvention include, but are not limited to surfactants, such as sodiumlauryl sulfate (SLS), poloxamer, sorbitan monoesters and glycerylmonooleates, as well as spicy ingredients, and others. The irritants arepreferably employed at about 0.01-10% by weight of the finalformulation, preferably 0.01-10% by weight, and most preferably about0.1-5% by weight.

In embodiments of the present invention, the irritant can deter abuseupon tampering with the transdermal delivery device. For example, if anabuser extracts and dries the ketamine, then the irritant is exposed anddiscourages inhalation of the ketamine mixed with the irritant, asinhalation (e.g., via snorting through the nose) will induce pain and/orirritation of the abuser's mucous membrane and/or nasal passagewaytissue.

Other suitable excipients useful in the preparation of transdermaldelivery devices are within the knowledge of those skilled in the art,and can be found in the Handbook of Pharmaceutical Excipients (7^(th)ed, 2012), the entire content of which is hereby incorporated byreference.

EXAMPLES Examples 1-5

The formulation of Examples 1-5 are disclosed below in Table 6.

TABLE 6 Ingredient Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Class Ingredient (wt %) (wt%) (wt %) (wt %) (wt %) Active Ketamine 20 25 25 25 25 IngredientPressure- DuroTak 387-2052 70 65 40 sensitive DuroTak 87-2677 55adhesive DuroTak 87-4098 40 Skin Oleyloleate 5 5 5 permeation Oleylalcohol 5 5 enhancer Levulinic acid 5 5 5 5 5 Diethylene glycol 5 5monoethyl ether Crystallization Polyvinyl 10 20 inhibitorspyrrolidone-co- vinyl acetate Polymethacrylate 20 Total 100 100 100 100100

The pressure sensitive adhesive (PSA) employed in Examples 1, 2, and 4was Duro-Tak 387-2052 (supplied by Henkel Adhesives). The PSA employedin Example 3 was Duro-Tak 87-2677 (Henkel Adhesives). The PSA employedin Example 5 was Duro-Tak 87-4098 (Henkel Adhesives). Persons skilled inthe art will understand that other known pressure sensitive adhesivescan be readily employed with the transdermal delivery devices of thepresent invention.

The skin permeation enhancer employed in Examples 4 and 5 was diethyleneglycol monoethyl ether, sold wider the tradename Transcutol P. Personsskilled in the art will understand that other known skin permeationenhancers can be readily employed with the transdermal delivery devicesof the present invention.

The crystallization inhibitor in Examples 3 and 4 was polyvinylpyrrolidone-co-vinyl acetate, sold under the tradename Kollidon VA 64(BASF Corporation). The crystallization inhibitor employed in Example 5was polymathacrylate-based polymer, sold under the tradename Plastoid B(Evonik Corporation). Persons skilled in the art will understand thatother known crystallization inhibitor enhancers can be readily employedwith the transdermal delivery devices of the present invention.

FIG. 5 is a comparison of the plasma concentration-time profile of a 0.5mg/kg dose of ketamine in a human subject following: (1) a 40-minutesingle IV administration; and (2) administration of a 24 hourtransdermal delivery device of the present invention according Example 2(a 9.4 cm² transdermal deli very device with a 3.75 mg/cm² permeationrate). Convolution analysis was applied in accordance with thepharmacokinetic parameters set forth in Fanta, et al., Eur. J. Clin.Pharmacol., 71:441-447 (2015). The transdermal delivery device accordingto Example 2 exhibits a lower C_(max), preferably less than about 30%,and more preferably less than about 20%, of the C_(max) from anequivalent IV dosage.

FIG. 6 discloses ketamine plasma concentration-time profiles for threesizes (10, 100 and 300 cm²) of the once-a-day transdermal deliverydevice of the present invention according to Example 2.

FIG. 7 discloses ketamine plasma concentration-time profiles for threesizes (10, 100 and 300 cm²) of the three times-a-day transdermaldelivery device of the present invention according to Example 2.

Skin permeation enhancers are incorporated in the transdermal deliverydevices of the present invention to ensure that sufficient ketamine canpenetrate through skin. Skin permeation studies were performed on thetransdermal delivery devices prepared according to Examples 1-5 usingFranz diffusion cells maintained at 37° C. The receptor medium wasphosphate buffered saline at pH 7.4, the receptor volume was 12 ml andthe permeation area was 1.767 cm². Human cadaver skin was used and thetests were performed in triplicate. A 1×1 inch transdermal deliverydevice was placed onto the donor side of the skin diffusion cells,adhered onto the skin, and the experiment was initiated with thereceptor medium being continuously mixed (stirring at 600 rpm). Samples(1.5 ml) of the receptor phase were obtained at 2, 4, 8, 12, 24, 48 and72 hours. The drug concentrations were quantitated using HPLC. Asdemonstrated in Table 6, Examples 1-5 of the present invention allprovide good skin permeability. The cumulative amounts of ketamine thatpermeated after 24 hours are shown in Table 7.

TABLE 7 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ketamine in transdermal 3.56 4.715.86 7.51 9.58 delivery device, mg/cm² 24 h Cumulative 1.21 3.72 2.621.74 0.73 Permeation, mg/cm²

FIG. 8 depicts in vitro skin permeability of the transdermal deliverydevices of the present invention according to Example 2 as shown by theFranz Diffusion Cell model.

Drug crystallization will retard drug release and skin permeability,reducing the efficacy of the transdermal delivery device. Drug crystalsshould not be formed in the transdermal delivery device over a periodapproximating the shelf life, i.e., for about 6 months or greater.Examples 1 and 2 showed instability, i.e. drug crystals were formed inthe adhesive drug matrix 4-7 days after preparation of the transdermaldelivery devices. Examples 3, 4 and 5, were found to be stable for atleast 4 weeks, i.e. within this period, no crystals were formed. Example5 was found to be stable for at least 6 months at conditions of 25° C.,60% RH.

Table 8 reports the stability data for the transdermal delivery devicesprepared according to Examples 1-5.

FIG. 9 depicts the stability of ketamine in a transdermal deliverydevice according to Example 5 after 0 months and after 6 months.

TABLE 8 Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Crystallization None None 10% 20% 20%Inhibitors Kollidon Kollidon Plastoid B VA 64 VA 65 Stability atCrystals Crystals Crystals Crystals No crystals 25° C./65% RH formed atformed at formed at formed at formed up to Day 10 Day 10 Month 3 Month 3Month 6

Example 6

Transdermal Delivery Device with Non-Segregated Abuse Deterrent Agents

Example 5 was modified to prepare a transdermal delivery device thatcontains 5 mg of denatonium benzoate and 200 mg of ketamine in theadhesive drug matrix. In vitro skin permeation studies showed that nodenatonium benzoate permeated the skin (because of its large molecularweight (447 DA) and the high melting point (170° C.). Nevertheless,ketamine showed excellent skin permeability (0.8 mg/cm² in 24 hours),indicating that incorporation of an abuse deterrent agent, such asdenatonium benzoate did not affect the skin permeation of ketamine.

In an extraction study to simulate attempted drug-abuse, transdermaldelivery devices prepared according to Example 6 were soaked for 60minutes in 100 ml of three different media: (1) 40% ethanol; (2) 70%isopropyl alcohol; and (3) acetone. All three media were assayed forketamine and denatonium benzoate using HPLC. More than 50% of theoriginal ketamine and more than 50% of the denatonium benzoate werefound in the media (i.e., the buttering agent extracted proportionallyto the amount of ketamine extracted), indicating the effectiveness ofusing denatonium benzoate as an abuse deterrent agent in the presentinvention.

Example 7

Transdermal Delivery Device with Abuse Deterrent Agents in a SegregatedLayer

Example 7 comprises a transdermal delivery device with an abusedeterrent agent in a segregated layer. The abuse deterrent agentemployed in Example 7 is a gelling agent which reacts with commonsolvents (e.g., water and alcohol) used to extract and abuse theketamine in the transdermal delivery device. The thickness of theadhesive-drug layer and the abuse deterrent layer are both about 2 toabout 5 mils. The transdermal delivery device according to Example 7 isprepared in a two-step process.

Step 1. Preparation of the Abuse Deterrent Layer

PolyOx 1105, propylene glycol, and PEG 4000 were mixed to form the abusedeterrent layer. The three ingredients were dissolved in a water/ethanolsolvent, followed by casting of the wet film directly on a sheet ofbacking layer, e.g., 3M's polyethylene film, Scotpak 1012. The wet filmis then dried at 60° C. for 30 min in a convective-air drying oven. Thecoating thickness of the abuse deterrent layer is about 3 mils. Anexample of a suitable abuse deterrent layer composition is disclosed inTable 9.

TABLE 9 Ingredient gm Wt % PolyOx WSR N-10 7.20 46.2% PolyOx 1105 3.6023.1% PEG 4000 2.80 17.9% Propylene Glycol 2.00 12.8% Ethanol Anhydrous*28.00 0.00% Putified Water* 57.00 0.00% Total 100.60  100% *evaporatedduring processing.

An abuse deterrent agent, such as Bitrex and sodium lauryl sulfate(SLS), may be incorporated into the abuse deterrent layer, preferablyfrom about 0.01-5% by weight of the final formulation, and mostpreferably from about 0.05-0.5% by weight of the final formulation.

Step 2. Preparation of Adhesive Drug Matrix Layer:

The adhesive drug matrix layer is prepared by casting the adhesive drugmatrix mix directly on the abuse deterrent layer (prepared in step 1),or onto a release liner and then laminated to the abuse deterrent layer.

DuroTak 87-4098 is weighed into a 100 ml beaker, and then mixed at lowspeed. Next, the Kollidon VA 64 and the ketamine are added to the mixer.The batch is mixed until all ingredients are dissolved. Then wet filmsare prepared at 3 mils thickness using a film casting applicator onrelease liner, such as 3M's 9744. The wet coating is air dried for 1hour, and then oven dried at 60° C. for 10 min. Finally, the laminate isdried onto the abuse deterrent layer, which was subsequently coated on3M's backing Scotpak 1012.

The laminated sheet can be die-cut into transdermal delivery devices ofvarious sizes, such as 10 cm², 20 cm², 100 cm², 300 cm² to obtain thedesired dosages of the drug.

An exemplary composition of the adhesive drug matrix is given in Table10.

TABLE 10 Ingredients Wt % Ketamine  15% vinylpyrrolidone-vinyl acetatecopolymers  20% (Kollidon VA 64) DuroTak 87-4098  65% Total 100%

Example 8

A transdermal delivery device according to Examples 7 is prepared withapomorphine, an emetic, in the abuse deterrent layer. After solventextraction by an abuser, the emetic can cause severe nausea if injected,snorted, or inhaled. Apomorphine is preferably employed in the presentinvention from about 0.05-5% by weight of the final formulation, andmost preferred from about 0.1-2% by weight.

Example 9

Example 9 was prepared in accordance with Example 7, with the exceptionthat the abuse deterrent agent is capsaicin. After being dissolved insolvents by an abuser, the ketamine solution containing capsaicin willcause a torturous burning sensation if snorted or inhaled, therebyreducing the abuse potential of the transdermal drug delivery device.

Examples 10

Table 11 provides additional techniques by which the abuse deterrentagents can be employed in the transdermal delivery device of the presentinvention.

TABLE 11 Potential Route of Manipulation/Abuse Abuse Deterrent AgentsExtraction with drinkable solvent Denatonium released when abused,co-precipitates (alcohol), followed by drinking with ketamine, andbitters the drinkable solvent Extraction with injectable medium, Gelforming agent will dissolve in medium, forming followed by injectionviscous liquid, which deters injection Extraction with solvent, SLS willco-precipitate with ketamine, and cause evaporation, followed bysnorting nasal mucosal irritation upon snorting Extraction with solvent,Denatonium released when abused, co-precipitates evaporation, followedby mixing and dries with ketamine, and bitters the subsequent withliquid and drinking drinking liquid

Example 11

In an embodiment of the present invention is prepared according toExample 7, in which the adhesive-drug layer comprises an adhesive and200 mg of ketamine, and the abuse deterrent layer comprises a gelforming agent comprising 7 mg of SLS and 5 mg of denatoniurn benzoate.

The foregoing description and examples have been set forth merely toillustrate the present invention and are not intended to be limiting.Since modifications of the described embodiments incorporating thespirit and substance of the invention may occur to persons skilled inthe art, the invention should he construed broadly to include allvariations within the scope of this application, including but notlimited to the appended claims and equivalents thereof.

1-5. (canceled)
 6. A method of treating major depressive disorderscomprising administration of a transdermal delivery device comprisingketamine, wherein the transdermal delivery device provides a ketaminepermeation rate of about 0.1-30 mg/day/cm2 of ketamine for about 8 hoursto about 168 hours.
 7. (canceled)
 8. A method of treating paincomprising administration of a transdermal delivery device comprisingketamine, wherein the transdermal delivery device provides a ketaminepermeation rate of about 0.1-30 mg/day/cm2 of ketamine for about 8 hoursto about 168 hours.
 9. (canceled)
 10. The method of claim 6, wherein thetransdermal delivery device provides about 0.1-30 mg/day/cm² of ketaminefor about 7 days.
 11. The method of claim 6, wherein the transdermaldelivery device provides about 0.1-30 mg/day/cm² of ketamine for about 1day.
 12. The method of claim 6, wherein the transdermal delivery deviceprovides about 0.1-30 mg/day/cm² of ketamine for about 3.5 days.
 13. Themethod of claim 6, wherein the transdermal delivery device providesabout 0.5-5 mg/day/cm² of ketamine for about 7 days.
 14. The method ofclaim 6, wherein the transdermal delivery device provides about 0.5-5mg/day/cm² of ketamine for about 1 day.
 15. The method of claim 6,wherein the transdermal delivery device provides about 0.5-5 mg/day/cm²of ketamine for about 3.5 days.
 16. The method of claim 6, wherein thetransdermal delivery device is about 10-300 cm².
 17. The method of claim6, wherein the transdermal delivery device is about 100-300 cm².
 18. Themethod of claim 6, wherein the transdermal delivery device is about10-100 cm².
 19. The method of claim 6, wherein administering thetransdermal delivery device provides reduced C_(max) compared toimmediate release administration of ketamine.
 20. The method of claim 6,wherein administering the transdermal delivery device provides ketamineplasma concentrations from about 0.4-4000 ng/ml for about 8-168 hours.21. The method of claim 6, wherein administering the transdermaldelivery device provides ketamine plasma concentrations from about10-200 ng/ml for treatment of major depressive disorders.
 22. The methodof claim 6, wherein administering the transdermal delivery deviceprovides ketamine plasma concentrations below 100 ng/ml for about 8hours to about 7 days, and which reduces the adverse side effect ofketamine when compared with plasma concentrations from immediate releaseketamine formulations.
 23. The method of claim 8, wherein administeringthe transdermal delivery device provides ketamine plasma concentrationsfrom about 50-1000 ng/ml for treatment of pain.
 24. The method of claim6, wherein administering the transdermal delivery device providesreduced plasma fluctuations over time when compared with plasmaconcentrations from immediate release ketamine formulations.
 25. Themethod of claim 6, wherein administering the transdermal delivery deviceprovides: (a) reduced C_(max) fluctuations, (b) reduced plasmaconcentration fluctuations, and (c) reduced adverse side effects, whencompared with ketamine plasma concentrations from immediate releaseformulations.
 26. The method of claim 6, wherein administering thetransdermal delivery device provides a C_(max) no greater than about 30%of the C_(max) from a dose equivalent immediate release ketamineformulation.
 27. The method of claim 6, wherein the ketamine is theR-enantiomer.
 28. The method of claim 6, wherein the ketamine is theS-enantiomer.
 29. A transdermal delivery device comprising ketamine,which is a drug-in-adhesive patch comprising a backing layer, anadhesive-drug layer, and a release liner, wherein the adhesive-druglayer comprises ketamine of 10-25% by weight and a pressure sensitiveadhesive, wherein ketamine is the only active ingredient in thetransdermal delivery device.